Scientists alter fentanyl, aim to make it less lethal, less addictive – Washington University School of Medicine in St. Louis

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The goal is to reduce the dangerous side effects of powerful opioid pain relievers

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Fentanyl, a powerful opioid pain reliever, is the leading cause of overdose death in the United States. In an effort to improve the drug’s safety profile without sacrificing its pain-relieving ability, a team of researchers led by scientists from the Center for Clinical Pharmacology at Washington University School of Medicine in St. Louis University of Health Sciences and Pharmacy studied the drug’s chemical properties and how it binds to opioid receptors on nerve cells. Changed the way of being

Their study, expressing manipulated opioid receptors in mice and cell lines, indicates that the modified drug is still an effective pain reliever but likely without many of the potentially fatal side effects. The research was published Nov. 30 in the journal Nature.

Although more studies are needed in additional animal models and in humans to evaluate fentanyl switching strategies, the research holds promise for developing safer opioid medications that relieve pain.

“Opioids, including fentanyl, are among the most effective pain relievers we have, but they have led to many accidental deaths, a situation that is simply tragic,” said the paper’s corresponding author, Sushruta Majumdar, PhD, an associate professor of anesthesiology at Washington University and the University of Associate Professor of Medicinal Chemistry and Pharmacology in Health Sciences and Pharmacy. “We are desperately looking for ways to maintain the analgesic effects of opioids, while avoiding dangerous side effects such as addiction and respiratory distress that often lead to death. Our research is still in its early stages, but we are excited about the possibility of leading to safer pain-relieving drugs.”

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Fentanyl is commonly used to manage severe pain in cancer patients and patients undergoing major surgery. It is 50 times stronger than heroin and 100 times stronger than morphine, and designer fentanyl is often mixed with other drugs such as heroin and oxycodone and sold on the street. More than 150 people die every day in the United States from overdoses from opioid drugs like fentanyl.

Like heroin and oxycodone, fentanyl binds to mu-opioid receptors on nerve cells. Once lodged in the receptor, drugs like fentanyl relieve pain but can lower blood pressure and slow breathing, potentially leading to suffocation and even death. Other side effects include euphoria, dizziness, confusion and sedation. Because of its potency, fentanyl is particularly lethal, even in very small amounts.

In modifying fentanyl, the researchers created a variation of the drug that still binds to the mu-opioid receptor but also involves a sodium ion binding site present on the receptor. Majumder said the study showed that by targeting the sodium binding site, the pathway by which fentanyl acts against pain was slightly altered, allowing the drug to retain most of its analgesic effects and reduce adverse effects.

When the modified drug was tested in mice that were exposed to a painful stimulus or in a mouse model of chronic pain, the drug retained its ability to relieve pain. In addition, rats were less likely to experience respiratory depression than rats due to standard formulations of fentanyl, and behavioral studies in rats suggested less abuse potential. While the results are encouraging, Majumder cautioned that more research is needed to understand the potential risks and benefits of modified fentanyl.

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The mu-opioid receptor belongs to a family of cellular receptors called G-protein coupled receptors, which are capable of binding hormones and signaling molecules in addition to opioid drugs.

“The idea that sodium ions, something we find in table salt, can modulate the activity of G-protein coupled receptors, such as these opioid receptors, is not new, but our group appears to be the first to successfully alter the chemistry. fentanyl so that it interacts with the sodium site of the receptor,” Majumder said.

And it turns out that many other drugs also target G-protein coupled receptors, suggesting that such drugs can also be modified to reduce their side effects by modifying the sodium binding site present on these targets.

“About one-third of all drugs currently on the market — from blood pressure drugs to diabetes drugs to painkillers like fentanyl — bind to different G-protein-coupled receptors, so it’s possible to make many drugs more effective, and to limit their side effects, they’re like this. By changing how it binds to receptors,” he said.

Others involved in the new research include 2012 Nobel laureate Brian Kobilka, MD, PhD, professor of molecular and cellular physiology at Stanford Medicine, who trained as a medical resident at Barnes-Jewish Hospital and Washington University School of Medicine in the early 1980s; Vsevolod Katrich, PhD, associate professor of quantitative and computational biology and chemistry at the University of Southern California; Georgios Skiniotis, PhD, professor of molecular and cellular physiology and structural biology at Stanford; and J.P. McLaughlin, PhD, professor of pharmacodynamics at the University of Florida.

Much of the work was conducted at the Center for Clinical Pharmacology, a collaboration between the University of Washington and the University of Health Sciences and Pharmacy. Center researchers have academic appointments at both institutions. The center’s focus is on finding better, safer and more effective ways to use prescription drugs to improve health. A primary focus has been to better understand and improve pain treatment.

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In future studies, the researchers plan to test their chemically modified fentanyl in other laboratory animals and develop a form of the drug that would work systemically like a pill instead of the current injectable version.

Fawzi A, et al. Structure-based design of bitopic ligands for the m-opioid receptor. Nature, 30 November, 2022.

This work was supported by the National Institute on Drug Abuse and the National Cancer Institute of the National Institutes of Health (NIH). Grant numbers include R33 DA045884, R01 DA042888, R01 DA007242, R37 DA036246, R33DA 038858, P01 DA035764, R21 DA048650, R00 DA528CA and P0387. Additional funding provided by an American Heart Association Postdoctoral Fellowship, the Mathers Foundation, the Brain and Behavior Research Foundation, and other funders (see paper for complete list).

About Washington University School of Medicine

WashU Medicine is a world leader in academic medicine, including biomedical research, patient care and educational programs with 2,700 faculty members. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among US medical schools, having grown 54% over the past five years, and with institutional investment, WASH commits more than $1 billion annually to basic and clinical research. Innovation and training. Its faculty practice is consistently among the top five in the nation, with more than 1,790 faculty physicians practicing at more than 60 locations and who are also on the medical staff of BJC Healthcare’s Barnes-Jewish and St. Louis Children’s Hospitals. WashU Medicine has a history of MD/PhD training, recently dedicated $100 million to renew scholarships and curriculum for its medical students, and is home to leading training programs in every medical subspecialty as well as physical therapy, occupational therapy and audiology. and communication sciences.


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